There is a significant unmet medical need for therapies to treat neurodegenerative disorders. Alzheimer's[unreadable] disease (AD) and Huntington's disease (HD), for example, have no cure or even an effective treatment.[unreadable] These two diseases alone cost the US healthcare system $100+ billion a year. SIRT1 is a member of the[unreadable] sirtuin family of NAD+-dependent deacetylases, which are thought to have evolved very early in life's history[unreadable] to enhance an organism's chances of surviving adversity and may underlie the neuroprotection and other[unreadable] health benefits provided by caloric restriction (CR). Hyperactivation of SIRT1 is responsible for the[unreadable] remarkable ability of neurons to survive long afer being cut in the case of the Wallerian mouse mutant[unreadable] (WldS). We and others have also found that SIRT1 protects neurons against death and dysfunction in[unreadable] models for HD, AD and ALS. Resveratrol (a SIRT1-activating molecule) or "STAC" can significantly delay[unreadable] neurodegeneration and cognitive decline in the p25-Tg mouse model of AD. Our lab has generated 20+[unreadable] analogs of resveratrol, some of which have improved stability and potency. We have also generated the first[unreadable] SIRT1 tissue-specific inducible transgenic mouse. In this proposal, we will investigate the mechanism by[unreadable] which SIRT1 provides protection against neurodegeneration and test whether SIRT1 activation can delay the[unreadable] progression of different two neurodegenerative disorders, namely AD and HD using mouse genetic models.[unreadable] Preliminary experiments indicate that SIRT1 works by suppressing apoptosis and increasing DNA repair, the[unreadable] latter of which is emerging as a possible contributor to brain aging and a variety of neurodegenerative[unreadable] disorders. The STACs and SIRT1 transgenic animals we have generated place us in a unique position to be[unreadable] able to test these hypotheses.[unreadable] Lay description: Ten percent of Americans over the age of 65 suffer from Alzheimer's disease, a disease[unreadable] estimated to cost approximately $100 billion annually. The SIRT1 protein is considered by many to possibly be a master[unreadable] regulator of the body's innate defenses against disease and debilitation. SIRT1 is somehow able to keep[unreadable] neurons healthy and alive when they would otherwise die. We aim to uncover the mechanism by which[unreadable] S1RT1 protects neurons and to develop molecules that stimulate the SIRT1 protein and provide protection[unreadable] against a variety of neurodegenerative diseases.